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BOR - Papers in Press, published online ahead of print November 24, 2004.
Biol Reprod 2004, 10.1095/biolreprod.104.036715
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BIOLOGY OF REPRODUCTION 72, 762–766 (2005)
DOI: 10.1095/biolreprod.104.036715
© 2005 by the Society for the Study of Reproduction, Inc.

Reduced Uteroplacental Perfusion Alters Uterine Arcuate Artery Function in the Pregnant Sprague-Dawley Rat1

Cindy M. Anderson2,3,4, Faye Lopez4, Hai-Ying Zhang4, Kristin Pavlish4, and Joseph N. Benoit4

College of Nursing3 Department of Pharmacology, Physiology and Therapeutics,4 School of Medicine and Health Sciences, University of North Dakota, Grand Forks, North Dakota 58202


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Evidence continues to implicate reduced placental perfusion as the cause of preeclampsia, initiating a sequence of events leading to altered vascular function and hypertension. The present study was designed to determine the influence of reduced uteroplacental perfusion pressure (RUPP) on the responsiveness of uterine arcuate resistance arteries. A condition of RUPP was surgically induced in pregnant Sprague-Dawley rats on Gestational Day 14. On Gestational Day 20, uterine arcuate arteries were mounted on a small-vessel wire myograph and challenged with incremental concentrations of vasoconstrictors and vasorelaxants for measurement of isometric tension. Compared to the sham-operated controls, uterine arteries from the RUPP group demonstrated an increased maximal tension in response to phenylephrine (P < 0.01); potassium chloride at 30 mM (P < 0.05), 60 mM (P < 0.01), and 120 mM (P < 0.01); and angiotensin II (P < 0.05). In arteries from the RUPP and sham-operated control groups, endothelium-dependent relaxation in response to acetylcholine (P < 0.05) and calcium ionophore (A23187; P < 0.05) was significantly reduced in the RUPP group compared to the sham-operated controls. Fetal growth indices, including litter size, fetal weight, and placental weight, were significantly reduced in the RUPP group compared to sham-operated controls, which is consistent with significant growth restriction. Data suggest that RUPP promotes hyperresponsiveness and impaired endothelium-dependent relaxation in uterine arcuate arteries, leading to intrauterine fetal growth restriction.

nitric oxide, placenta, pregnancy, uterus


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Pregnancy is a normal physiologic process that requires a synchronized adaptation of multiple organ systems. Increased perfusion is characteristic of the hemodynamic alterations commonly seen in successful pregnancy [1]. Vessels are remodeled to form a low-resistance arteriolar system, which serves to promote delivery of a greatly increased blood and oxygen supply to the developing fetus [2, 3]. Increased endothelium-mediated release of vasodilators in response to vasoconstrictors serves to promote perfusion to the fetus under potentially adverse conditions [4].

Inadequate remodeling and cytotrophoblast invasion of the spiral arteries are believed to promote the abnormal placental development seen in preeclampsia [5–7], as reviewed by Granger [8]. These affected resistance arteries remain anatomically intact and undilated with an intact nerve supply, promoting their ability to retain responsiveness to vasoconstrictors [9]. This incomplete remodeling contributes to an inadequate response to the increasing demand of blood supply to the fetus, decreased uteroplacental perfusion, increased placental ischemia, and areas of infarction.

Alteration in endothelial function as a direct result of the cascade of events precipitated by improper placental development is believed to be the cause rather than the effect of preeclampsia. Vascular endothelial dysfunction is hypothesized to result from placental ischemia and release of placental products [10–12]. Reduction in the blood flow to organs and the development of endothelial dysfunction precedes the clinical manifestation of disease [13]. Clinical signs of preeclampsia become evident in later pregnancy, most often during the third trimester, and include hypertension and proteinuria [14].

The typical response of the smooth muscle of arterioles to increased transmural pressure is vasoconstriction in an effort to maintain myogenic basal tone [15]. This response, though important under most conditions for local control of blood flow, is detrimental to fetal and placental perfusion. The risk to the fetus resulting from decreased placental perfusion includes a reduction in the size of the placenta and inadequate nutrients and oxygen required for normal fetal development [16]. The inadequate provision of nutrients prevents normal growth and development of all organ systems, contributing to low-birth-weight and small-for-gestational-age infants [17].

Animal models are useful in the study of vascular function, because they provide an opportunity to directly measure vascular smooth muscle force generation. The reduced uteroplacental perfusion pressure (RUPP) model is one of the most authentic animal models currently available for the study of pregnancy-induced hypertension, with pathologic changes stimulated by reduced uteroplacental perfusion, as in human preeclampsia. The effects of reduced uteroplacental perfusion have been documented in conduit and systemic resistance arteries in this model [18]. The present study was designed to determine the local influence of RUPP on uterine artery function and fetal growth in this rat model of human preeclampsia.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Animals and Breeding

All procedures involving animals were conducted with approval of the University of North Dakota Animal Care Committee in accordance with the Guide for the Care and Use of Laboratory Animals [19]. Male and nulliparous female Sprague-Dawley rats were purchased from Charles River Laboratories (Wilmington, MA) for use in the present study. Male rats were used for breeding purposes only. Animals were housed in an environmentally controlled vivarium (group housed before surgery and individually housed after surgery). A 12L:12D photoperiod was provided, and animals were allowed free access to water and standard pellet diet. Individual female rats (weight, 250–300 g) were paired with a single male and mated overnight for a maximum of 4 days or until the seminal plug was identified, which was considered to be Gestational Day 1. Experiments were performed on Gestational Day 20, just before the anticipated time of delivery, which usually occurs on Gestational Days 21–23. Rats were killed by cardiac transection while under anesthesia on the day that experiments took place.

Reduced Uteroplacental Perfusion Pressure

On Gestational Day 14, animals underwent a sham procedure or a surgical procedure to create RUPP. Following administration of buprenorphine (0.25 mg/kg) as a preemptive analgesia, an abdominal midline surgical incision was made under anesthesia with 2% isofluorane delivered by an anesthesia apparatus. The lower abdominal aorta was isolated below the renal arteries, and a silver clip (inner diameter, 0.203 mm) was placed above the iliac bifurcation to reduce uterine perfusion pressure by approximately 40% [20]. Adaptive increase in blood flow to the placenta was limited by restricting circulation to the branches of both the right and left ovarian arteries that supply the uterus using a silver clip (inner diameter, 0.100 mm). Sham operations were conducted on dams in the control group, in which the vessels were isolated but not clipped. Incisions were closed in layers using appropriate suture material.

Isometric Force Measurement

Rats were anesthetized and killed on Gestational Day 20. While under anesthesia, fetal pups and placentas were removed, placed on ice, and weighed. The uterine arcade was removed and immediately placed in cold physiologic saline solution (PSS) containing 119 mM NaCl, 4.7 mM KCl, 2.5 mM CaCl2, 1.2 mM MgSO4, 25 mM NaHCO3, 1.2 mM NaH2PO4, 0.03 mM EDTA, and 5.5 mM glucose adjusted to pH 7.4. Uterine arcuate arteries were excised and dissected free of surrounding tissues. Uterine arcuate arteries were selected for investigation in an effort to determine the local vascular response of RUPP and the effects on fetal growth.

Arterial segments (length, 2 mm) were threaded onto two 40-µm tungsten wires and mounted on a small-vessel wire myograph for measurement of isometric force and tension in a 5-ml bath of PSS as originally described by Mulvany and Halpern [21]. Arterial dimensions were measured with the vessel set to internal circumference (mean wall thickness [w1], mean wire thickness [d], mean distance between the inner edges of the wires [f1], mean vessel segment length [g1], wall tension [T], and wall stress [{sigma}]). Measurements were calculated as follows: internal circumference, L1 = ({pi} + 2)d + 2f1; wall tension, T = F/2g; active wall tension, {Delta}T = Tactive – Trelaxed; active wall stress, {Delta}{sigma} = {Delta}T/w; effective lumen diameter, 1 = L/{pi}; effective transmural pressure, p = 2{pi}T/L; and effective active pressure, {Delta}p = pactive – prelaxed.

With constant exposure to 95% O2/5% CO2, vessels were slowly warmed to 37°C and normalized [21] to achieve optimized internal circumference for development of tension. Normalized uterine arcuate arteries were set at 0.9-fold the internal circumference when internal pressure reached 50 mm Hg (L1 = 0.9L50). Following an equilibration period of 30 min, arteries were challenged with phenylephrine (PE; 10 µM) for a minimum of two consecutive priming doses, followed by washing with warmed PSS between doses.

At the end of a 30-min equilibration period, vessels were exposed to increasing, cumulative concentrations of each of the following: PE (Sigma), 10–9 to 10–3.5 M; potassium chloride (KCl; Sigma Chemical Co., St. Louis, MO), 4.7, 30, 60, and 120 mM; angiotensin II (ICN Biomedicals, Costa Mesa, CA), 10–12 to 10–6 M; acetylcholine chloride (ACh; Sigma), 10–10 to 10–4 M; calcium ionophore (A23187; Sigma), 1, 3, 10, and 30 nM; and sodium nitroprusside (SNP; Sigma), 10–10 to 10–6 M. Relaxation response was determined through exposure of each vessel segment to PE (3 µM) for preconstriction before exposure to ACh, SNP, and A23187. Vessels were thoroughly washed with PSS between doses and allowed to equilibrate for 30 min before each subsequent dose-response. Concentration-effect curves were generated for each constrictor and relaxant to determine vascular responsiveness. Five rats were used in each group for contraction responses. Relaxation concentration-effect curves were generated using four rats per group.

Statistical Analyses

Isometric tension in uterine arcuate arteries was displayed graphically and measured using concentration-effect curves generated from exposure to vasoactive agent in a small-vessel wire myograph. Maximal tension (Tmax) and the drug concentration eliciting a 50% response (EC50) were derived and used for comparison between experimental RUPP and control sham-operated groups. Data were expressed as the mean ± SEM. Statistical analyses were performed to determine group differences using a one-tailed, unpaired Student t-test. A value of P < 0.05 was considered to be significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Vasoconstrictive agents were used to determine both receptor and voltage-mediated vascular responses. {alpha}1-Receptor-mediated contraction was determined after uterine arcuate arteries were exposed to cumulative amounts of PE. Responses of uterine arcuate arteries from experimental and control groups responded in a concentration-dependent manner (Fig. 1). No significant differences were observed in the EC50 values of the two groups (RUPP: 0.55 ± 0.20 µM, n = 5; sham: 0.56 ± 0.22 µM, n = 5), but the maximal tension in the RUPP group (7.67 + 0.70 mN/mm) was significantly increased (P < 0.01) as compared to the sham-operated group (4.86 + 0.58 mN/mm).



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  		FIG. 1. Vascular response of uterine arteries to increasing doses of PE. Maximal tension was increased in the RUPP group (R; n = 5) as compared to the sham-operated controls (S; n = 5)

Uterine arteries were challenged with incremental, cumulative concentrations of KCl to determine voltage-gated contractile responses (Fig. 2). Significant increases in maximal tension (Tmax) were measured in the RUPP group as compared to the sham-operated controls at 30 mM (2.8 ± 0.08 vs. 0.98 ± 0.20 mN/mm, P < 0.05), 60 mM (4.08 ± 0.47 vs. 1.94 ± 0.32 mN/mm, P < 0.01), and 120 mM (4.13 ± 0.43 vs. 2.24 ± 0.37 mN/mm, P < 0.01) concentrations, with no difference observed between groups at physiologic concentration (4.7 mM). A similar pattern of increased maximal tension (P < 0.05) was identified in angiotensin II-mediated arterial responses (Fig. 3). This finding is consistent with vascular responses seen in human preeclampsia, which is characterized by the retained responsiveness to angiotensin II. The increase in maximal tension in the RUPP group (6.06 ± 0.47 mN/mm, n = 4) was greater than that seen in the sham-operated group (3.73 + 0.99 mN/mm, n = 4), but no differences in EC50 values were identified.



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  		FIG. 2. Effects of cumulative concentrations of KCl in uterine arteries from RUPP and sham-operated animals. Maximal tension was increased in the RUPP animals treated at 30, 60, and 120 mM as compared to the sham-operated controls. *P < 0.05, **P < 0.01



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  		FIG. 3. Concentration-effect curve of uterine artery exposed to increasing concentrations of angiotensin II. Maximal tension was increased in the RUPP group as compared to the sham-operated controls. *P < 0.05

To assess endothelial and vascular smooth muscle function, both endothelium-dependent and -independent relaxation responses were determined. Uterine arcuate arteries were preconstricted with PE (3 µM) and subjected to increasing concentrations of ACh (Fig. 4), an endothelial-dependent relaxant. The uterine artery in the RUPP group demonstrated significant impairment of relaxation in response to ACh (EC50: RUPP vs. sham, 0.072 ± 0.05 vs. 0.017 ± 0.004 µM; P < 0.05), suggesting the potential for endothelial dysfunction in this group. To corroborate these findings, uterine arteries were exposed to low concentrations (1–30 nM) of A23187, which promotes the endothelial-dependent release of nitric oxide (NO) [22]. The RUPP uterine arteries (EC50: 3.02 ± 0.85 nM, n = 4) were significantly less responsive to A23187 (P < 0.05) as compared to sham-operated controls (EC50: 1.45 ± 0.13 nM, n = 4) (Fig. 5), which is consistent with the findings seen with ACh.



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  		FIG. 4. Vascular response of uterine arteries to increasing doses of ACh. Uterine arcuate arterial responsiveness of the RUPP group was significantly less (R; EC50: 0.072 ± 0.05 µM) than in the sham-operated controls (S; EC50 0.017 ± 0.004 µM). *P < 0.05



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  		FIG. 5. Effects of calcium ionophore on uterine arteries from RUPP and sham-operated rats on Gestational Day 20. The RUPP uterine arteries (n = 4) were less responsive than the uterine arteries from the sham-operated controls (n = 4). *P < 0.05

Endothelial-independent responses were examined to determine if the impaired relaxation responses to the endothelial-dependent agents were caused by vascular smooth muscle dysfunction rather than endothelial dysfunction. Uterine arcuate arteries were challenged with increasing concentrations of SNP, an endothelial-independent relaxant, and the changes in tension were recorded. In the RUPP group, the uterine artery relaxation response was significantly greater (EC50: 6.6 ± 3.15 nM, n = 4) as compared to the sham-operated controls (EC50: 23.44 ± 4.34 nM, n = 4) (Fig. 6), confirming vascular smooth muscle function.



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  		FIG. 6. Concentration-effect curve for SNP response in uterine arteries in the RUPP and sham-operated groups. Relaxation response in the RUPP group (n = 4) was significantly increased (R; EC50: 6.6 ± 3.15 nM) as compared to the sham-operated controls (S; EC50: 23.44 ± 4.34 nM; n = 4). *P < 0.05

To determine the influence of RUPP and uterine arcuate artery function on fetal growth, determinations of fetal weight, placental weight, and litter size were made from the litters of 13 RUPP experimental dams and 15 sham-operated control dams on Gestational Day 20. Fetuses with exposure to RUPP experienced significant reductions in placental weight (P = 0.006), fetal weight (P = 0.006), and litter size (P = 0.04) as compared to fetuses from sham-operated control dams, confirming the presence of intrauterine fetal growth restriction.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The development of maternal hypertension, altered renal function, and fetal growth restriction as a direct result of induced perfusion reductions have been demonstrated clearly by other labs [18, 23–27]. The RUPP model serves as an authentic animal model of preeclampsia, in that it mimics the events that occur in the human condition during the third trimester as a response to reduced placental perfusion. Maternal hypertension, altered renal function, and fetal growth restriction represent common manifestations of preeclampsia in both humans and this animal model. The RUPP model provides an opportunity to study the vascular effects of preeclampsia through direct examination of resistance arteries to determine vascular smooth muscle function, which are studies not possible in humans. To our knowledge, this is the first report of functional impairment in the uterine arcuate artery in the RUPP Sprague-Dawley rat model. The reported results are consistent with similar findings in conduit arteries, and they provide further evidence for endothelial dysfunction induced by RUPP in resistance arteries.

Determination of the functional responses of the uterine arcuate artery in this rat model of RUPP was the major aim of the present study. During the initial characterizations of this model, endothelin was determined to be important in the mediation of hypertension [28]. We have demonstrated the presence of endothelial impairment in uterine arcuate arteries in response to RUPP. The development of endothelial dysfunction as a direct response to decreased placental perfusion pressure explains the mechanism of progressive vasoconstriction, hyperresponsiveness, and impaired relaxation of uterine arcuate arteries [10].

The fetal consequences of impaired relaxation and hyperresponsiveness in the uterine artery are consistent with those seen in human preeclampsia and serve as an important contributor to fetal intrauterine growth restriction. The vascular responses to endothelium-dependent mechanisms provide important insights regarding the functional ability of the endothelium in the RUPP and sham-operated animals. For these studies, ACh and A23187 were used to promote the release of NO from the endothelium, and SNP was employed as an NO donor. The results of vascular function studies with ACh and A23187 demonstrated impaired endothelium-dependent vasodilation. This finding suggests the presence of endothelial dysfunction, and it indicates impaired release of NO from the endothelium through well-characterized mechanisms. The role of NO-mediated relaxation of the rat uterine artery is critical to promotion of adequate blood flow to the fetoplacental unit, with the significance of this contribution increasing progressively with gestation [29]. In addition to endothelium-dependent relaxation responses, SNP was used to determine endothelium-independent responses. The enhanced relaxation identified in vessels after exposure to SNP indicated that the ability of the vascular smooth muscle to respond to NO was not impaired, further implicating an impaired endothelium. These findings are consistent with those reported by Cooke and Davidge [30] in the uterine arteries of pregnant mice. The increased relaxation effect of SNP in the RUPP group suggests the development of a compensatory response to counter the effects of endothelial dysfunction.

The organ-specific nature of vascular responsiveness is of particular interest in the study of pregnancy and preeclampsia. Promotion of perfusion to the uterus and protection from hypoxic insult is critical to fetal survival and is significantly affected by vascular responsiveness. The vascular bed of the uterus during pregnancy is remodeled in an effort to promote perfusion to the fetoplacental unit despite changes in endogenous neural (i.e., {alpha}-adrenergic) and humoral stimuli. Inadequate remodeling of the uterine artery vessels during placental development in humans not only initiates endothelial dysfunction but also promotes enhanced responsiveness and limited relaxation ability of uterine arteries, similar to the vascular pathology evidenced in the RUPP model.

We suggest that the decreased NO response of these uterine arteries is responsible for the increased vasoconstrictor responses in this model of RUPP, and we implicate the impaired endothelial-dependent relaxation response as the major contributor to increased vascular resistance. Altered parameters of fetal growth also can be explained by the development of increased vascular resistance of the uterine arcuate artery, affecting the morbidity and mortality of the resulting pups. The present study illustrates the contribution of uteroplacental perfusion to vascular dysfunction, and it adds to the evidence supporting use of the RUPP model as an authentic model for human preeclampsia. Reduced placental perfusion is not only the end but also the means toward the progressive nature of preeclampsia.


   FOOTNOTES
 
1 Supported by the American Heart Association Predoctoral Fellowship (C.M.A.) and the National Institute of Digestive, Diabetes, and Kidney Disease (J.N.B.) DK51430. Back

2 Correspondence: Cindy M. Anderson, Box 9025, Fifth and Harvard Street, College of Nursing, University of North Dakota, Grand Forks, ND 58202-9025. FAX: 701 777 4096; cindyanderson{at}mail.und.nodak.edu Back

Received: 30 September 2004.

First decision: 11 October 2004.

Accepted: 9 November 2004.


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 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
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